| Autor: |
McConoughey, SJ, Basso, M, Niatsetskaya, ZV, Sleiman, SF, Smirnova, NA, Langley, BC, Mahishi, L, Cooper, AJL, Antonyak, MA, Cerione, RA, Li, B, Starkov, A, Chaturvedi, RK, Bea, MF, Coppola, G, Geschwind, DH, Ryu, H, Xia, L, Iismaa, SE, Pallos, J, Pasternack, R, Hils, M, Fan, J, Raymond, LA, Marsh, JL, Thompson, LM, Ratan, RR |
| Jazyk: |
angličtina |
| Rok vydání: |
2010 |
| Zdroj: |
McConoughey, SJ; Basso, M; Niatsetskaya, ZV; Sleiman, SF; Smirnova, NA; Langley, BC; et al.(2010). Inhibition of transglutaminase 2 mitigates transcriptional dysregulation in models of Huntington's disease. EMBO Molecular Medicine, 2(9), 349-370. doi: 10.1002/emmm.201000084. UC Irvine: Retrieved from: http://www.escholarship.org/uc/item/9485z8k5 |
| DOI: |
10.1002/emmm.201000084. |
| Popis: |
Caused by a polyglutamine expansion in the huntingtin protein, Huntington's disease leads to striatal degeneration via the transcriptional dysregulation of a number of genes, including those involved in mitochondrial biogenesis. Here we show that transglutaminase 2, which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes; transglutaminase 2 interacts directly with histone H3 in the nucleus. In a cellular model of HD, transglutaminase inhibition de-repressed two established regulators of mitochondrial function, PGC-1a and cytochrome c and reversed susceptibility of human HD cells to the mitochondrial toxin, 3-nitroproprionic acid; however, protection mediated by transglutaminase inhibition was not associated with improved mitochondrial bioenergetics. A gene microarray analysis indicated that transglutaminase inhibition normalized expression of not onlymitochondrial genes but also 40% of genes that are dysregulated in HD striatal neurons, including chaperone and histone genes. Moreover, transglutaminase inhibition attenuated degeneration in a Drosophila model of HD and protectedmouse HD striatal neurons from excitotoxicity. Altogether these findings demonstrate that selective TG inhibition broadly corrects transcriptional dysregulation in HD and defines a novel HDAC-independent epigenetic strategy for treating neurodegeneration. © 2010 EMBO Molecular Medicine. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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